| Cab molecules -> Monitor Keywords |
|
|
 
Cab moleculesCab molecules description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080096810, Cab molecules. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001]The present invention relates to CAB molecules, ADEPT constructs directed against CEA and their use in therapy. BACKGROUND [0002]Traditional therapeutic molecules circulate freely throughout the body of patients until they are removed from circulation by the liver or another mechanism of clearance. Such non-targeted molecules can exert pharmacological effects indiscriminately on a wide range of cells and tissues. Indiscriminate targeting can cause serious side effects in a patient. The problem may be particularly acute when the molecule is highly toxic (e.g., in the case of a chemotherapeutic agent where the therapeutic window, the difference between an efficacious and injurious or even lethal dose, can be small). [0003]In recent years, researchers have attempted to develop compounds that specifically affect particular groups of cells, tissues or organs. Most of the compounds target a particular tissue by preferentially binding a particular target molecule displayed by the tissue. By preferentially affecting targeted cells, tissues or organs, the therapeutic window can be increased, which in turn increases the opportunity for a successful treatment regimen and/or reduces the occurrence of side effects. [0004]Preferential binding is employed in antibody-directed enzyme prodrug therapy (ADEPT). See, e.g., Xu et al., 2001, Clin Cancer Res. 7:3314-24.; Denny, 2001, Eur J Med Chem. 36:577-95. In ADEPT, an antibody or antibody fragment is linked to an enzyme capable of converting an inactive pro-drug into an active cytotoxic agent. An ADEPT conjugate is administered to a patient, and the conjugate is localized to a target tissue via antibody/antigen binding. The prodrug is subsequently administered, and the prodrug circulates throughout the patient's body but causes few or no side effects because the prodrug is in the inactive form and is activated by the ADEPT antibody-enzyme conjugate only in the vicinity of the target tissue. Thus, a relatively low concentration of active drug is present throughout the body, but a relatively high concentration of active drug is produced in the vicinity of the target tissue, increasing the therapeutic window of the toxin at the desired site. [0005]In ADEPT, the antibody or antibody portion of a construct binds to an antigen to achieve localization, so selecting the proper antigen is important (e.g., an antigen that has a high tumor/normal expression profile). An antigen of particular interest frequently found on the cell surface in cancer tissues is carcinoembryonic antigen (CEA). CEA was first described by Gold and Freedman, J. Exp. Med., 121, 439-462, (1965). CEA is highly expressed in tumor tissue and also found at a lower concentration in some normal organs, particularly in the digestive tract. [0006]Many antibodies to tumor antigens cross-react with related antigens. Systemic application of a MAb that is cross-reactive with a related antigen must be avoided to preclude risk of potentially severe side effects. Accordingly, the development of antigen-specific monoclonal antibodies for in vitro and in vivo diagnosis and therapy requires a good knowledge of the number, quality and biodistribution of related cross-reactive antigens. Careful immunochemical characterization of the MAb to be used is required with respect to its specificity and affinity for the target antigen and for related antigens. [0007]Murine MAb T84.66 (ATCC Accession No. BH 8747) IgG1, k shows a high affinity constant to CEA and no cross reactivity to other members of the CEA gene family. A significant potential side effect of ADEPT therapy is the development of antibodies against the targeted enzyme during therapy. The production of human anti-mouse antibodies (HAMA) leads to reduced efficiency of the MAb and to potentially serious manifestations of acute and chronic allergic complications for the patient. See Levy, et al. Ann. Rev. Med. 34:107-116 (1983); Houghton, et al. Proc. Natl. Acad. Sci. USA, 82:1242-1246 (1985) and Sears, et al. J. Biol. Resp. Modifiers 3:138-150 (1984). Antibody formation has been observed during a clinical trial of a CEA-directed antibody-enzyme conjugate two weeks after treatment, which prevented subsequent rounds of treatment [Napier, M. P., S. K. Sharma, C. J. Springer, K. D. Bagshawe, A. J. Green, J. Martin, S. M. Stribbling, N. Cushen, D. O'Malley and R. H. Begent (2000) Clin Cancer Res 6, 765-72, Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma]. [0008]The risk of eliciting an immune reaction is high for microbial proteins. The use of human enzymes for ADEPT has been investigated in pre-clinical studies [Smith, G. K., S. Banks, T. A. Blumenkopf, M. Cory, J. Humphreys, R. M. Laethem, J. Miller, C. P. Moxham, R. Mullin, P. H. Ray, L. M. Walton and L. A. Wolfe, 3rd (1997) J Biol Chem 272, 15804-16, Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate]. Although the risk of antibody formation can be reduced for human protein as compared to microbial protein, human proteins can also elicit immune reactions when administered to people. The consequences of eliciting an immune reaction against a human protein can be very significant, as such a treatment could trigger an auto-immune disease. [0009]The risk of eciciting an immune reaction may be great for an ADEPT construct that contains at least two potential risks: the antibody portion and the enzyme portion. SUMMARY OF THE INVENTION [0010]The present invention relates to CAB molecules, ADEPT constructs directed against CEA and their use in therapy, especially with prodrugs as described herein. The molecules of the current invention have been preferably deimmunized and do not elicit an immune response and can be produced in high yield. [0011]In a first aspect, the CAB molecule comprises an antibody/enzyme conjugate, wherein the antibody portion binds to CEA. In a preferred embodiment, the enzyme comprises a beta-lactamase. [0012]In a preferred embodiment, the CAB molecule has an unmodified amino acid sequence. In a preferred embodiment, the CAB molecule has an amino acid sequence modified from the amino acid sequence set forth in SEQ ID NO:2, and the modification is located at least one of positions 12, 72, 283 or 586, wherein position numbering is with respect to SEQ ID NO:2 as shown in FIG. 4. In a preferred embodiment, the CAB molecule has both of the following modifications: 12 and 72. In a preferred embodiment, the CAB molecule has all of the following modifications: 12, 72, 283 and 586. [0013]In a preferred embodiment, the CAB molecule has at least one of the following modifications: A12S, R72G, K283A or S586A, wherein position numbering is with respect to SEQ ID NO:2 as shown in FIG. 4. In a preferred embodiment, the CAB molecule comprises a CAB1.11 molecule, the CAB1.11 molecule comprising the following modifications: A12S and R72G. In a preferred embodiment, the CAB molecule comprises a CAB1.11i molecule, the CAB1.11i molecule comprising the following modifications: A12S, R72G, K283A and S586A. [0014]In a preferred embodiment, the CAB molecule comprises CAB 1.10 having SEQ ID NO:2, CAB1.11 having SEQ ID NO:7 or CAB1.11i having SEQ ID NO:8. [0015]In a second aspect, the invention is drawn to a nucleic acid encoding a CAB molecule as set forth herein. In a third aspect, the invention is drawn to treating a subject in need thereof, comprising administering to the subject a CAB molecule, as provided herein, and a prodrug that is a substrate of the CAB molecule. In a fourth aspect, the invention is drawn to a pharmaceutical composition comprising a CAB molecule. BRIEF DESCRIPTION OF THE FIGURES [0016]FIG. 1 sets forth unmodified sequences disclosed in the invention. FIG. 1A (SEQ ID NO:1) sets forth the amino acid sequence of the T84.66 antibody as described in Shively et al. and as disclosed in the invention provided herein; FIG. 1B sets forth the nucleotide sequence of the T84.66-derived antibody (SEQ ID NO:3); FIG. 1C sets forth the amino acid sequence for BLA (SEQ ID NO: 11); FIG. 1D sets forth the nucleotide sequence for BLA (SEQ ID NO:12); FIG. 1E sets forth the amino acid sequence for the 1.10 (SEQ ID NO: 2) construct that is T84.66 fused to BLA and includes a linker; FIG. 1F sets forth the nucleotide sequence for the 1.10 construct (SEQ ID NO:4). Underlining indicates the scFv portion of the molecule, and italics indicate the linker between the vl and vh portions of the scFv. [0017]FIG. 2 sets forth the modified CAB 1.11 antibody portion of the current invention. FIG. 2A sets forth the amino acid sequence that has been modified and comprises a CAB 1.11 antibody portion (SEQ ID NO:5); FIG. 2B sets forth the nucleotide sequence sequence (SEQ ID NO:6) that has been modified and comprises a CAB1.11 antibody portion. [0018]FIG. 3 sets forth amino acid sequence of the deimmunized BLA portion (SEQ ID NO:13). Mutations from unmodified BLA (provided in FIG. 1) are shown in bold; numbering has been retained to remain consistent with the CAB1.11i construct. [0019]FIG. 4 sets forth sequences for the CAB1.11 and CAB1.11i molecules. FIG. 4A sets forth the amino acid sequence of the CAB1.11 molecule (SEQ ID NO:7), which includes an antibody portion modified to improve expression, as described in the Examples, and also includes the BLA portion; FIG. 4B sets forth the nucletotide sequence of the CAB1.11 molecule (SEQ ID NO:9); FIG. 4C sets forth the amino acid sequence of the CAB1.11i molecule (SEQ ID NO:8), which includes the deimmunized BLA portion, as set forth in the Examples; FIG. 4D sets forth the nucletotide sequence that encodes the CAB1.11i molecule (SEQ ID NO:10), FIG. 4E sets forth the nucleotide sequence that encodes the plasmid, pHR19.2. In the Figure showing the CAB1.11i molecule, the scFv portion of the molecule has been underlined. The four mutations described in the Examples herein have been underlined. The linkers provided herein have been italicized. Two of the mutations are in the scFv portion of the molecule, and two of the mutations are in the BLA portion of the molecule. [0020]FIG. 5 shows the plasmid map for pHR19.2. Continue reading about Cab molecules... Full patent description for Cab molecules Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Cab molecules patent application. Patent Applications in related categories: 20090291893 - Compositions for the prevention and treatment of neuroinjury and methods of use thereof - A method for preventing or ameliorating secondary neuronal injury and inflammation following traumatic brain injury (TBI) is disclosed. The method comprises the step of administering into a subject in need of such treatment an effective amount of a pharmaceutical composition containing a neuregulin (NRG), a variant of NRG, or an ... 20090291885 - Conjugated toxin peptide therapeutic agents - Disclosed is a composition of matter comprising an OSK1 peptide analog, and in some embodiments, a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises the composition and a pharmaceutically acceptable carrier. Also disclosed are DNAs encoding the inventive composition of matter, an expression vector comprising the DNA, and host cells ... 20090291889 - Diagnostic assay and method of treatment for miscarriage risk or premature birth involving macrophage inhibitory cytokine-1 (mic-1) - Methods for diagnosing risk of miscarriage and/or premature birth, foetal abnormalities, cancer (e.g. prostate cancer) and inflammatory disease (e.g. rheumatoid arthritis) are disclosed which involve determining abnormal levels of macrophage inhibitory cytokine-1 (MIC-1) in a body sample or, otherwise, determining the presence of a MIC-1 variant protein. Also disclosed are ... 20090291890 - Factor vii polypeptides that are modified and uses thereof - Modified factor VII polypeptides and uses thereof are provided. Such modified FVII polypeptides include Factor VIIa and other forms of Factor VII. Among modified FVII polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities. Hence, such modified polypeptides are therapeutics. ... 20090291896 - Genes encoding novel proteins with pesticidal activity against coleopterans - The invention provides nucleic acids, and variants and fragments thereof, obtained from strains of Bacillus thuringiensis encoding δ-endotoxins having pesticidal activity against pests of the order Coleoptera. The invention further provides mutagenized nucleic acids that have been modified to encode endotoxins having improved pesticidal activity and/or altered pest specificity. Particular ... 20090291895 - Methods and compositions for the treatment of inflammatory diseases - Compositions and methods for treating inflammatory disorders are provided. ... 20090291894 - Methods for treating progressive cognitive disorders related to neurofibrillary tangles - The described invention provides methods for treating or preventing progression of a progressive cognitive disease, disorder or condition, and methods for improving resilience of cognitive function in a subject in need thereof. ... 20090291897 - Methods for treating unwanted weight loss or eating disorders by administering a trkb agonist - This invention relates to methods for treating unwanted body weight loss (such as cachexia), eating disorders (such as anorexia nervosa), or opioid-induced emesis by peripheral administration of a trkB agonist. The invention also relates to compositions and kits comprising a trkB agonist. ... 20090291888 - Modulators of tnf receptor associated factor (traf), their preparation and use - A DNA sequence encoding a protein capable of binding to a tumor necrosis factor receptor-associated factor (TRAF) molecule, TRAF-binding proteins, their isoforms, analogs, fragments and derivatives encoded by the DNA sequence, their methods for the production of the DNA sequences and proteins, and the uses for the DNA sequence and ... 20090291884 - Proteins for use in diagnosing and treating infection and disease - The present invention describes a composition comprised on cystatin A and at least one histone used in diagnostic tools and for the treatment of diseases associated with reduced T helper cell counts such as HIV-1 infection, AIDS, ARC, multiple sclerosis, chronic fatigue syndrome, heumatoid arthritis, Alzheimer's disease, dermatitis, type 1 ... 20090291887 - Proteins of the sdf-1-family for the manufacturing of a medicament - Use of a protein of the SDF-1-family for the manufacturing of a medicament for the improvement of the plasticity and/or regeneration of axons upon their lesion. ... 20090291892 - Slpa as a tool for recombinant protein and enzyme technology - Disclosed are a recombinant DNA molecule encoding a fusion protein comprising a SlpA chaperone and a target polypeptide wherein human FK506 binding proteins (FKBPs) are excluded as target polypeptides, a corresponding expression vector encoding said fusion protein as well as host cells transformed with said expression vector. Also disclosed are ... 20090291886 - Transmucosal delivery of peptides and proteins - Provided are methods and compositions for enhancing the transmucosal absorption of bioactive peptides and proteins. More particularly, the invention provides compositions for enhancing the transmucosal absorption of bioactive peptides and proteins, such as exendin-4, PYY, PYY3-36, and GLP-1 and their analogs and derivatives, wherein the compositions comprise an absorption enhancing ... 20090291891 - Vegf variant that lacks vegfr-1 binding activity and its use in promotion of re-endothelization and prevention of in-stent restenosis - A VEGF145 polypeptide devoid of a VEGFR-1 binding activity and methods of making and using same in preventing and/or treating restenosis are provided. ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Cab molecules or other areas of interest. ### Previous Patent Application: Nitric oxide-blocked cross-linked tetrameric hemoglobin Next Patent Application: Diastereomeric peptides useful as inhibitors of membrane protein assembly Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Cab molecules patent info. IP-related news and info Results in 0.23978 seconds Other interesting Feshpatents.com categories: Electronics: Semiconductor , Audio , Illumination , Connectors , Crypto , 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
